Published online before print June 15, 2006, doi: 10.1161/01.RES.0000232324.87983.4b
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Submitted on December 30, 2005
Revised on May 17, 2006
Accepted on June 2, 2006
Haplotypes of the Caspase-1 Gene, Plasma Caspase-1 Levels, and Cardiovascular Risk
Stefan Blankenberg *;
From the Departments of Medicine II (S. Blankenberg, H.J.R., C.B., R.S., T.M.) and Clinical Chemistry and Laboratory Medicine (K.J.L.), Johannes Gutenberg-University Mainz, Germany; INSERM U525 (T.G., O.P., S. Barbaux, V.N., F.C., L.T.), Université Pierre et Marie Curie/Faculté de Médecine Pitié-Salpêtrière, Paris, France; Department of Epidemiology and Public Health (F.K., A.E.), Belfast, UK; and Greater Glasgow Health Board (C.M.), Glasgow, UK.
* To whom correspondence should be addressed. E-mail: stefan.blankenberg{at}uni-mainz.de.
Caspase-1 processes the interleukin (IL)-1
and IL-18 inactive precursors to the biologically active cytokines that are known to have proatherogenic effects. The present study investigated the genetic variability of the CASP1 gene and plasma levels of caspase-1 in relation to cardiovascular risk. In Europeans, 3 tag SNPs captured 4 common haplotypes of the CASP1 gene. Among these, the Ain6 allele of the G +7/in6A polymorphism was less frequent in 246 cases with myocardial infarction and a parental history of disease than in 253 controls free of familial history of disease (0.13±0.02 versus 0.20±0.02; P=0.005). However, in a larger case/control study (n=1774), these effects are borderline restricted to the UK population. In a prospective cohort of 1168 patients with coronary artery disease followed up during a median period of 6.0 years, the Ain6 allele exhibited a borderline association with future cardiovascular death (hazard ratio [HR]: 0.64, 0.41 to 1.01; P=0.053) and was associated with lower serum IL-18 levels (P=0.014). Baseline caspase-1 levels in the top quartile of the distribution were predictive of cardiovascular deaths (HR=3.62, 1.81 to 7.27; P=0.0003 compared with the bottom quartile). Finally, in vitro assays of allelic imbalance showed that the CASP1 haplotype carrying the Ain6 allele was associated with a lower mRNA expression. These results indicate that caspase-1 levels are predictive of future cardiovascular death in patients with coronary artery disease. The role of CASP1 genetic variations in the susceptibility to myocardial infarction requires further investigation.
Key words: caspase-1 • inflammation • prognosis • coronary disease • genetics
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